An important role of the immune system is to identify and eliminate tumour cells. When a tumour first forms, the immune system recognizes it as foreign and generates specialized T cells to attack and kill it. However, tumours have evolved a number of mechanisms that prevent the immune system from being able to function properly, resulting in cancer progression. One of the mechanisms by which tumours escape from the immune system is by secreting chemicals that promote the generation of cells that inhibit T cells from carrying out their normal functions. The presence of these suppressive cells is one of the most common reasons current cancer therapies fail. Melisa Hamilton is investigating a specific subset of these suppressive cells, called myeloid immune suppressor cells (MISCs). Previous research has shown that the protein known as SHIP is important in regulating the survival and proliferation of myeloid cells (white blood cells). Hamilton’s research is focused on investigating the specific role SHIP plays in MISC development and function. With a better understanding of how tumours stimulate the development of MISCs and how these cells suppress the immune system, researchers can design targeted therapies to prevent the formation and function of MISCs. These therapies would greatly increase the ability of the immune system to attack and eradicate tumours and would be especially effective in combination with current cancer immunotherapy treatments to improve cancer patient outcomes.
Program: Trainee
Analysis of a carbohydrate active pneumococcal virulence factor
While the bacterium Streptococcus pneumoniae is found in 10-40 per cent of healthy people with no ill effects, it is the cause of common diseases including pneunomia, meningitis, and ear infections. Unfortunately, more and more penicillin-resistant strains of S. pneumonia are becoming prevalent, and these strains are also developing resistance to other antibiotics. There are still a few antibiotics available to treat S. pneumoniae, but resistance to these drugs will also certainly emerge. New, more effective ways to treat bacterial infections are urgently required. Bacteria have adapted the ability to use different carbohydrates, or sugars, for a number of biological processes such as metabolism. S. pneumoniae has a number of protein enzymes devoted to carbohydrate metabolism, including a pathway dedicated to degrading (breaking down) the sugar fucose. Certain proteins in this pathway have been found to be important in some aspect of S. pneumoniae infection and disease. Melanie Higgins is focusing her research on a protein called GH98. GH98 is found on the outside of the bacteria and is thought to be the first step in this fucose degradation pathway. In order to better understand how this enzyme works, Higgins will first determine the three-dimensional structure of GH98. From these structures, she will develop synthetic inhibitor molecules that keep GH98 from functioning. Her work will answer whether S. pneumoniae can still infect host cells and spread disease in the absence of GH98. If these inhibitors are proven effective, they could become a novel treatment for S. pneumoniae infections, providing clinicians more options for treating a number of bacterial diseases.
ZIP-5/Bach1 antagonizes SKN-1/Nrf2 in development and longevity
Many of the genes involved in aging are also involved in embryonic development. These same genes have been linked to cancer development (carcinogenesis). An example of such a gene is daf-2, which is the worm version of the human insulin and insulin-like growth factor receptor. When this gene is mutated in worms (C. elegans), they live twice as long. Victor Jensen studies genes regulated by daf-2 in order to find new genes implicated in longevity. He has identified a gene called zip-5 that, when mutated, allows worms to live 25-35 per cent longer and remain healthier. zip-5’s ability to extend longevity depends on the function of another gene called skn-1. SKN-1 has several functions: it contributes to embryonic gut development, it regulates stress response and is implicated in increased longevity that results from dietary restriction. The human counterpart to SKN-1 is called Nrf2, which regulates stress resistance in human cell lines. Nrf2 also provides a chemoprotective effect against carcinogenesis, injury and inflammation. The action of Nrf2 is opposed by a gene called Bach1 – the human counterpart of the worm zip-5 gene. Inhibiting Bach1 allows for easier activation of Nrf2 target genes, resulting in a stronger chemoprotective effect in cancer. Jensen’s research genetically characterizes this antagonistic relationship and identifies the novel role of zip-5 in longevity and development. He is working to determine whether the Bach1/Nrf2 relationship is parallel to the zip-5/skn-1 relationship in C. elegans, and whether it explains zip-5’s effect on longevity. He hopes his research will reveal a new role for zip- 5/Bach1 in development and longevity, and open the door to new studies looking at how Bach1 inhibition affects carcinogenesis and aging.
Somatic and gametic loss of imprinting (LOI) in mammalian development: studies using a novel imprinted transgene on the mouse distal chromosome 7 (MMU7) imprinted region
Genetic inheritance primarily results from the interplay of dominant and recessive genes between two parents. With certain genes, however, gene expression is parent-of-origin-specific: these genes will always be expressed from either the maternal or paternal chromosome. This process is known as genomic imprinting, which creates a mark, or “imprint”, on the chromosome. Gametes are reproductive cells, such as sperm or eggs, which contain a single set of chromosomes. During their maturation, their imprints are erased then re-established. Between the erasure and re-establishment phases is a transitional loss of imprinting (LOI) state. Problems with the erasure or re-establishment of imprints in gametes can result in a number of human genetic disorders, including Prader-Willi, Angelmann, Silever-Russell, and Beckwith-Wiedemann Syndromes. In non-gamete tissues, on the other hand, imprints are generally thought to be maintained throughout life and LOI is often considered to be an abnormal condition. Both loss of epigenetic marks and loss of parent-specific gene expression are observed frequently in many types of cancers, but whether this is a cause or an effect of this abnormal growth is unclear. Meaghan Jones was previously supported by MSFHR for her early PhD studies in genomic imprinting. She is now working to determine more about what causes LOI events in both gametic and non-gametic tissues. She is using a model of Beckwith-Wiedemann Syndrome to determine when LOI occurs in cells, with the hope of pinpointing factors that can cause LOI. An understanding of normal LOI in development could help alleviate the risk of imprinting defects, and could improve effectiveness of medical technologies including assisted reproductive technologies, stem cells, nuclear transfer, and cloning.
Studies toward the total synthesis of the analgesic natural product chimonanthine and its analogues
A major area of concern for Canada’s health system is the treatment of chronic pain, which affects more than 18 per cent of Canadians and costs the health system close to $10 billion per year. More people are disabled by chronic pain than cancer or heart disease. New structurally-novel analgesics (painkillers) with unique modes of action have proven promising. One class of these molecules are the pyrrolidinoindolines, which are alkaloids (naturally occurring compounds produced by living organisms, many known for their medicinal properties). The alkaloid (-)-chimonanthine has recently been extracted from the leaves of the wintersweet, a flowering plant originating from China. This compound has been found to exhibit analgesic effects. Unlike other opiods, such as cocaine, heroin, morphine, and codeine, chimonanthines do not possess addictive properties. Using novel techniques in synthetic chemistry, Baldip Kang is working to synthesize (-)-chimonanthine. This work is a precursor to developing analogues for this compound – drugs that differ in minor aspects of molecular structure from the parent drug, synthesized so that they have more potent effects or fewer side effects. He’s focusing on determining the most efficient and cost-effective way to synthesize the molecules. He and colleagues will collaborate with a pharmaceutical company to test the analogues in pre-clinical trials, determining modifications to the structure that will further enhance the drug’s effectiveness. Through the efficient synthesis of (-)-chimonanthine and its analogues, Kang’s research promises new ways to treat chronic pain ailments.
The physiological role of P-glycoprotein in the gastrointestinal absorption of cholesterol
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among Canadians, accounting for an estimated 36 per cent of premature deaths. The majority of these CVD-related deaths result from ischemic heart disease (insufficient blood supply to the heart), which is often caused by plaque building up on the inside of blood vessels (atherosclerosis). As tobacco use has declined, elevated low-density lipoprotein (LDL) cholesterol levels have emerged as the major risk factor for the development of atherosclerosis. Treatment of elevated cholesterol has traditionally involved a drug regime of blood cholesterol-reducing statins, coupled with diet and lifestyle changes. However, increasing research evidence is driving health agencies to further lower their recommended target levels for low-density lipoprotein (LDL) cholesterol. These reduced levels may not be achievable with traditional interventions, requiring the development of new combination therapies. Inhibiting the absorption of cholesterol from the gastrointestinal tract is an attractive target for combination therapy with statins. Stephen Lee is investigating a transporter protein that is produced in the intestinal tract during the process of cholesterol absorption and processing. While several preliminary studies have implicated this protein in the cholesterol absorption process, none have investigated how this process is affected by diet. Stephen will examine the role of the protein on the absorption of cholesterol among mice fed one of four specific diets with precise fat and cholesterol contents. The proposed research may lead to the discovery of a new pharmacological target for future therapies that work with statin treatments to reduce cholesterol levels.
Identification of causal genetic alterations involved in the progression of epithelial cancers
Of the 227,000 newly diagnosed cancer cases in Canada in 2007, approximately 80 per cent were some type of carcinoma. Carcinomas (epithelial cancers) include a vast array of common cancers such as lung, breast, prostate, colorectal, oral, esophageal and cervical cancers. Patients with early stage cancer show the best response to therapies and exhibit the greater survival rate compared to those with the advanced stage disease. However, with current screening techniques, the majority of patients present with advanced stage disease at the time of diagnosis, limiting treatment options. The disruption of genes is responsible for cancer development. However, the accumulation of gene disruptions during cancer progression makes it difficult to distinguish which disruptions are the initiating events in this process. The discovery of these initiating events are crucial for gaining a better biological understanding of how cancer progresses. Conventional methods can only detect large DNA disruptions that may contain many genes, hindering precise identification of the genes responsible for cancer development. MSFHR funded William Lockwood for his early PhD research. He’s now continuing his comparison of DNA profiles of normal cells against cancerous cells. By labelling normal and tumour DNA with different dyes, he will be able to investigate the genetic changes that occur in progressing stages of cancer, in order to retrace the evolving patterns of gene disruption during cancer development. By distinguishing the initiating events, Lockwood’s research will shed light on the pathways driving the progression of cancer cells. This could lead to the identification of biomarkers to predict which early stage cancers are prone to develop into advanced tumours.
Regulation of the BACE1 gene expression in Alzheimer's Disease pathogenesis
Alzheimer’s disease (AD) is the most common neurodegenerative disorder leading to dementia, affecting approximately 10 per cent of the Canadian population over the age of 65. One of the pathological hallmarks of AD is increased deposition of the beta-amyloid protein, which forms amyloid plaques in the brains of AD patients. This is caused by dysfunction of the BACE enzyme, which regulates processing of the amyloid precursor protein to generate beta-amyloid proteins. Levels of the BACE enzyme have been shown to be elevated in Alzheimer’s. Philip Ly is interested in studying the underlying molecular mechanisms regulating the BACE enzyme expression and activity. He is studying a region of the BACE gene called the BACE promoter. This region has been demonstrated to be important for BACE expression. However, the regulations at the level of BACE gene transcription – the first step in the expression of the genetic information – remain elusive. Using a series of molecular and biochemical approaches, Ly is examining the transcriptional controls that regulate BACE gene expression in neurons. He is also examining if specific mutations in these transcription factors affect BACE expression and contribute to AD pathogenesis. Ly’s research will be the first to thoroughly characterize the transcriptional regulation of the BACE1 and the role of abnormal gene expression in AD pathogenesis. In addition to providing much needed information regarding signal transduction in amyloid precursor protein processing, these studies have important pharmaceutical implications, such as potential development of BACE enzyme inhibitors to improve treatment of Alzheimer’s disease.
T Cell Therapy of Breast Cancer; Challenges and Opportunities
T cell therapy is a promising approach in cancer treatment that aims to use the body’s own immune system to rid itself of cancer. The therapy involves isolating T cells that react to the tumour from a patient’s blood, expanding their numbers in culture and infusing them back into the patient, with the expectation that the T cells will recognize and destroy cancer cells throughout the body. This approach has yet to be applied clinically to breast cancer. MSFHR funded Michele Martin’s early PhD work using an innovative mouse mammary tumour model to study this approach for future use in human breast cancer. By infusing tumour-reactive T cells, she has been able to induce complete tumour regression of about 37 per cent of tumours, an unprecedented result compared to other forms of immunotherapy. However, the remaining tumours show partial regression or no regression at all. Martin now seeks to understand why some tumours are resistant to this treatment. Intriguingly, while all regressing tumours demonstrate heavy infiltration with T cells after treatment, many non-regressing tumours show no infiltration at all. Martin’s hypothesis is that many resistant tumours are able to physically exclude T cells. Her research will determine the molecular factors behind the physical mechanisms contributing to a tumour’s exclusion of these T cells, and test whether she can disrupt the tumour environment to facilitate the effective infiltration of T cells. The information gathered from Martin’s genetic analysis of infiltrated and uninfiltrated/resistant tumours will provide valuable data for defining the molecular barriers to T cell infiltration, and could point to ways to overcome these barriers.
Identification and therapeutic modulation of protein targets in dysfunctional innate immune networks associated with hyperinflammation and microbial susceptibility in cystic fibrosis and inflammatory …
Inflammation is a normal biological response initiated by the immune system to help control and contain infections. Inflammatory diseases occur when defects arise in the immune system pathways that co-ordinate either the detection of pathogens, or the subsequent biological response. Single defects in various critical points on these pathways can lead to profoundly abnormal biological outcomes. When defects in critical points in these immune networks are present, two different scenarios with similar outcomes can occur. In some instances, this can result in a response that is insufficient (hypoinflammatory) for clearing foreign microbes from the body, increasing the risk of lethal infections. Alternately, the inflammatory response can be overly robust (hyperinflammatory), leading to chronic inflammation and tissue damage that impairs the immune response. Examples of diseases with hyperinflammatory phenotypes include, cystic fibrosis (CF) and inflammatory bowel disease (IBD). Matthew Mayer is studying the immune systems of children and adults with these diseases. His goal is to identify new proteins in these dysfunctional inflammatory pathways that could serve as potential drug targets. In addition to treating these immune diseases, such drugs could also be used to treat bacterial infections in otherwise healthy individuals by enhancing their immune systems. This research could lead to new therapies for patients who suffer from inherited hyperinflammatory disease. It could also advance the discovery of new, non-antibiotic drugs that could be used to fight off bacterial infections.